Local
Distance
Along specified path Nerves
Via general routes Blood
Via ECF, Gap junctions, ECM...
PARACRINE MEDIATORS
AUTOCRINE MEDIATORS
Secreted by one cell & acts upon adjacent cells or surrounding extracellular matrix [ECM]
Secreted from a cell and acts on the same cell
Paracrine Autocrine MediatorsChemically they are classified into
MONOAMINESHistamineSerotonin …etc
PEPTIDESContractants Angiotensin EndothelinNPYVasopressin
Relaxants Kinines ANPTachykinins [SP]VIP ….etc
EICOSANOIDSProstaglandinsProstacyclinesThromboxane A2
Leukotrienes …etc
PURINESATP / ADPAdenosine
NO OTHERSCytokinesChemokineGrowth Factors….etc.
Paracrine Autocrine MediatorsGeneral Features
Act mostly on: smooth muscles (SMC) [vascular (VSMC) or non vascular (NVSMC)] nerve endings [> nonadrenergic non-cholinergic (NANC) co-transmission] + heart + exocrine glands + CNS …etcExist either:
Preformed & stored in tissues & released by a stimulus [Monamines (histamine), most peptides ]
Formed de novo in response to a stimulus [NO, eicosanoids, some peptides, cytokines] ]
Their presence is either:Constitutive: present all times, to share in normal basic functional regulation within the cells (eNOS / COXI ) Inducible: only present upon demand i.e. gets expressed [gene transcription, mRNA formation and ribosomal translation into protein](iNOS / COXII)
DRUGS Acting OnParacrine Autocrine Mediators
Nitric Oxide Angiotensin & Bradykinin
Eicosanoids Histamines
I
II
By the end of this lecture you will be able to:Recognize the role of NO in cellular communication.Classify the different NOS availableExpand on its formation, actions termination and pharmacological
modulation.Identify role of angiotensin in body homeostasis and local regulation. Explain its formation, target receptors, feedback regulatory actions,
breakdown, intersection with the kinin system and pharmacological modulation.
ILOs
DRUGS Acting OnParacrine Autocrine Mediators
Part I
Nitric Oxide
Nitric Oxide Is a highly diffusible stable gas
Synthesis
L-arginine + O2 NO + Citrulline + H2O
Nitric oxide synthase (NOS)
NADPH, FAD, CaCAM
Type I [n-NOS]
Neuronal NOS
Type III [E-NOS]Endothelial
NOS
Type II [I-NOS]Inducible NOS
Cytosol ofNeuronal cells
Bound to membrane of endothelial cell [EC], platelets …etc.
Cytosol of macrophage, neutrophil, kupffer cells … etc
Constitutive
Constitutive Inducible
Neuronal messengerCytoprotective
Relaxation of VSMCCytoprotective
Immunocytotoxicity
NOS Isoforms
Shear Stress or Agonists as; Ach, histamine, bradykinin, …..when bind to receptors intracellular Ca activate eNOS NO formation
Nitric Oxide
PARACRINE
PARACRINEPARACRINE
AUTOCRINE
Role of NO in blood vessels Relaxation of VSMC (Vasodilatation) + Cytoprotection on ECs
Nitric OxideAction
Activate PKG &Ca Inactivate MLCKPrevent actin myosin cross link No contractionRELAXATION
Endothelial Cell [EC]
1.VasodilatationDiffuse to VSMCBinds soluble GCChange GTP to cGMP
Site of formation
Vascular Smooth Muscle [ VSMC]
MLCK-
Diffu
sion
2. Cytoprotectionplatelet aggregationinflammatory cell recruitment Cholesterol deposition…etc.
PARACRINE
AUTOCRINEPARACRINE
Termination of action
Nitric OxideBy formation of 1. Stable analogues with proteins containing SH ….2. Free radical Peroxynitrite in oxidative stress
By break down of its downstream signal [cGMP]by PDE to form GMP
BV
Drugs modulating Nitric Oxide
1. Express eNOS: Statins, Estrogen CVS Cytoprotection
2. Act as NO donners: a. Nitrates >Venulodilators in angina b. Na Nitroprusside Arteriolar dilator in hypertension
3. Prevent breakdown of PDE: Selective PDE5 Inhibitors; Sildenafil Erectile dysfunction
Angiotensin
Endothelium, brain &
Angiotensinogen (Ag)Other Proteolytic Enzymes
ChymaseEndoperoxida
se
A vasoconstrictor peptide
Synthesis
Angiotensin [Ag]Precursor is Angiotensinogen; a plasma -globulin synthesized in the liver.
Secreted by renal juxtaglomerular apparatus
AT1
AT2
Blood Pressure Renal Blood flow
RAAS
PARACRINE
PARACRINE
ENDOCRINE
ALDOSTERONE
Suprarenal Gland
InotropyChronotropy
ActionAngiotensin
ALDOSTERONE
Ag II
Na retention HypertrophyFibrosis
ADH
ThirstSNS
activation
VasoconstrictionRemodeling =Hypertrophy
Fibrosis
Ag IIAg II
Ag II
Ag II
Blood Pressure
Angiotensin
AgII acted upon by peptidases
aminopeptidases (angiotensinase)
to Ag III [a less active] & then to fragmentation products
Termination of action
Ag II
BP BF [b2 ] Propranolol
Clonidine
Drugs modulating
RENIN InhibitorsAliskiren
ACE InhibitorsLisinopril
ARBsCandisartan
ADOSTERONE Antagonists
Spirinolactone Eplerenone
VASOPEPTIDASE IsOmapatrilat
INHIBITION OF RAAS SYSTEM is beneficial in treatment of:
Hypertension (hypertrophy)Heart Failure (hypertrophy & fibrosis) Diabetics (Protect the kidney)
Angiotensin
Inactive metabolites
Kinins Bradykinin is a vasodilator peptides
Synthesis
Action Vasodilatation Inflammation & Exudation Pain (sensory nerves) Exocrine gland secretion
Termination of action
KallidinBradykinin
Plasma Kallikrin
TissueKallikrin
Aminopeptidase
Inactive metabolites
KininogenFrom liver
ACE & Neutral Endopeptidase
(NEP)
KininsDrugs modulating . Action bradykinin mediated pain NSAIDs
Breakdowntheir concentration ACE Inhibitors VASOPEPTIDASE Is
Antihypertensive drugs
L-arginine + O2 NO + Citrulline + H2O
(eNOS)
BK R
Bradykinin
Vasodilatation
Inactive metabolites
ACE Inhibitors
ACE
AT1
AT2
ACE InhibitorsRamipril
ARBsCandisartan
Inhibit activation of AgI to AGII + decrease degradation of bradykininDifference between ACE Is & ARBs action
Block action of AgII on AT1 in VSMCs that is causing vasoconstrictionThe AgII act on non-blocked AT2 on endothelial cells causing vasodilatation
DRUGS Acting OnParacrine Autocrine Mediators
GOOD LUCK